Kunanusornchai Wanlop, Witoonpanich Bhee, Tawonsawatruk Tulyapruek, Pichyangkura Rath, Chatsudthipong Varanuj, Muanprasat Chatchai
Department of Physiology, Faculty of Science, Mahidol University, Rama VI Road, Rajathevi, Bangkok 10400, Thailand.
Department of Orthopedics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Rama VI Road, Rajathevi, Bangkok 10400, Thailand.
Pharmacol Res. 2016 Nov;113(Pt A):458-467. doi: 10.1016/j.phrs.2016.09.016. Epub 2016 Sep 17.
Synovial inflammation plays an important role in the early pathogenesis of osteoarthritis (OA). Chitosan oligosaccharide (COS) has been shown to activate AMPK and suppress inflammatory responses in intestinal epithelial cells. This study aimed to investigate the effect of COS on AMPK activation and synovial inflammation using both primary cultures of synoviocytes and a rabbit model of anterior cruciate ligament (ACL) transection-induced OA. COS induced AMPK activation in both rabbit and human synoviocytes. The mechanism of COS-induced AMPK activation involves an increase in the ADP/ATP ratio but not calcium/calmodulin-dependent protein kinase kinase beta (CaMKKβ). Interestingly, COS suppressed the TNFα-induced iNOS and COX-2 expression via an AMPK-dependent mechanism in both rabbit and human synoviocytes. Importantly, oral administration of COS (10mg/kg/day) induced AMPK activation and alleviated signs of inflammation including COX-2 expression in the synovium of a rabbit ACL transection model. Taken together, our results indicate that COS suppresses synovial inflammation in vitro and in vivo via AMPK activation. COS may be useful in the prevention of OA.
滑膜炎症在骨关节炎（OA）的早期发病机制中起重要作用。壳寡糖（COS）已被证明可激活AMPK并抑制肠道上皮细胞中的炎症反应。本研究旨在利用滑膜细胞原代培养物和前交叉韧带（ACL）横断诱导的OA兔模型，研究COS对AMPK激活和滑膜炎症的影响。COS在兔和人滑膜细胞中均诱导了AMPK激活。COS诱导AMPK激活的机制涉及ADP/ATP比值的增加，但不涉及钙/钙调蛋白依赖性蛋白激酶激酶β（CaMKKβ）。有趣的是，COS通过AMPK依赖性机制在兔和人滑膜细胞中均抑制了TNFα诱导的iNOS和COX-2表达。重要的是，口服COS（10mg/kg/天）可诱导AMPK激活，并减轻兔ACL横断模型滑膜中包括COX-2表达在内的炎症迹象。综上所述，我们的结果表明，COS通过激活AMPK在体外和体内抑制滑膜炎症。COS可能对预防OA有用。
